Cardiac Physiology — Cardiac Cycle

Electrical-Mechanical Coupling and Chamber Mechanics

• The sinoatrial (SA) node spontaneously depolarizes, generating the P wave on ECG, which corresponds to atrial systole. Atrial contraction increases ventricular filling by approximately 20-30%, known as the "atrial kick," which becomes critically important in conditions requiring enhanced preload (exercise, heart failure, atrial fibrillation with rapid ventricular response)
• Atrial depolarization triggers atrioventricular (AV) node conduction (PR interval, 0.12-0.20 seconds), allowing appropriate delay for ventricular filling before ventricular activation
• The QRS complex (0.06-0.10 seconds) represents ventricular depolarization, initiating ventricular systole and myocardial contraction via excitation-contraction coupling (calcium entry through L-type channels, calcium-induced calcium release from sarcoplasmic reticulum, actin-myosin cross-bridge cycling)

Ventricular Systole: Isovolumetric Contraction and Ejection Phases

• Isovolumetric contraction (first 50-80 ms of ventricular systole): Ventricular pressure rises rapidly without change in ventricular volume, as the mitral valve closes (generating the S1 heart sound) but the aortic valve remains closed. This phase represents the steepest portion of the left ventricular pressure-volume curve and is reflected in dP/dt_max (maximum rate of pressure rise)
• Rapid ejection phase: When left ventricular pressure exceeds aortic pressure (typically 80 mmHg), the aortic valve opens and blood is ejected. Peak systolic pressure is achieved, and approximately 60-70% of stroke volume is ejected in this phase. The T wave appears on ECG, representing ventricular repolarization
• Reduced ejection phase: Ventricular pressure falls as ejection continues at a slower rate. The aortic valve closes when ventricular pressure falls below aortic pressure, generating the S2 heart sound (aortic component). Ejection fraction (EF), the percentage of end-diastolic volume ejected, is approximately 50-70% in healthy individuals; reduced EF defines systolic dysfunction

Ventricular Diastole: Isovolumetric Relaxation and Filling Phases

• Isovolumetric relaxation: Immediately after aortic valve closure, ventricular pressure declines without change in volume (both mitral and aortic valves closed). Ventricular pressure must fall below atrial pressure for mitral valve opening. This phase is energy-dependent, requiring active calcium reuptake into the sarcoplasmic reticulum via SERCA2a (sarcoplasmic/endoplasmic reticulum calcium-ATPase) and calcium extrusion via the Na+/Ca2+ exchanger. Impaired relaxation (increased Tau, the relaxation time constant) defines diastolic dysfunction independent of systolic function
• Rapid ventricular filling (RVF): The mitral valve opens when left atrial pressure exceeds left ventricular pressure. Blood rapidly fills the ventricle due to the pressure gradient and elastic recoil of the ventricle (suction effect). Approximately 70-80% of ventricular filling occurs during RVF, represented as a rapid descent (y-descent) in atrial pressure tracings
• Atrial contraction (late diastole): Occurs during the final 20-30% of diastole and contributes the "atrial kick," important in maintaining adequate preload. In atrial fibrillation, loss of coordinated atrial contraction reduces stroke volume by 15-25%
• End-diastolic pressure-volume relationship (EDPVR): Ventricular pressure at end-diastole reflects chamber stiffness; increased stiffness (restrictive physiology, hypertrophy, fibrosis) elevates filling pressures and may cause pulmonary congestion

Pressure-Volume Loop and Work of the Heart

• The left ventricular pressure-volume loop graphically demonstrates the cardiac cycle: the area enclosed represents stroke work (pressure × change in volume). The loop's position and shape reflect contractility (steepness of systolic segment), afterload (aortic pressure resistance), and preload (ventricular volume)
• Contractility is reflected in the maximum elastance (slope of the end-systolic pressure-volume relationship, ESPVR) and is load-independent, distinguishing true contractile function from changes in afterload or preload
• Preload (end-diastolic volume/pressure) determines stroke volume via the Frank-Starling mechanism: increased preload stretches myocardial fibers to a more optimal length for cross-bridge overlap, increasing contractile force. However, excessive preload causes pulmonary edema; inadequate preload reduces stroke volume
• Afterload (resistance to ejection, approximated by aortic pressure or systemic vascular resistance) inversely relates to stroke volume; increased afterload reduces ejection fraction and increases end-systolic volume, rightward shifting the pressure-volume loop

Valve Dynamics and Phonocardiography

• S1 (first heart sound): Represents near-simultaneous closure of the mitral valve (louder, M component) and tricuspid valve (softer, T component, heard earlier at lower left sternal border). The sharp closure occurs because ventricular pressure rapidly exceeds atrial pressure during isovolumetric contraction
• S2 (second heart sound): Represents closure of the aortic valve (A2, heard earlier at right upper sternal border) and pulmonary valve (P2, heard later at left upper sternal border). Physiologic splitting of S2 occurs during inspiration (increased right ventricular filling delays P2 closure)
• S3 (ventricular gallop): Occurs in early diastole (RVF phase) and represents rapid ventricular filling hitting a stiff or dilated ventricle. S3 is normal in children and young adults (high-pitched) but abnormal in adults >40 years, suggesting heart failure or acute mitral regurgitation
• S4 (atrial gallop): Occurs during atrial contraction against a stiff ventricle (late diastole), heard immediately before S1. S4 represents decreased ventricular compliance from hypertrophy, ischemia, or hypertension; absent in atrial fibrillation

• Systolic dysfunction: Conditions reducing contractility or increasing afterload (acute myocardial infarction, cardiomyopathy, hypertension, aortic stenosis)
• Diastolic dysfunction: Conditions impairing relaxation or increasing stiffness (left ventricular hypertrophy from hypertension, restrictive cardiomyopathy, ischemia, aging)
• Valvular disease: Mitral stenosis prolongs RVF; aortic stenosis prolongs isovolumetric contraction; regurgitation alters pressure-volume loops
• Arrhythmias: Atrial fibrillation eliminates atrial contraction; premature beats alter filling time and preload; heart block prolongs AV interval

Normal Cycle Findings (Baseline for Comparison)

• Normal heart rate: 60-100 bpm at rest; rate-dependent diastolic shortening at faster rates primarily affects diastole, reducing diastolic filling time
• Normal heart sounds: S1 physiologically splits at lower left sternal border (M before T); S2 physiologically splits during inspiration (A2 before P2); no additional sounds
• Normal pulse pressure: Approximately 40 mmHg (120/80 mmHg systolic/diastolic), reflecting arterial compliance and ejection velocity
• Normal cardiac output: 4-8 L/min at rest (5 L/min average); cardiac output = heart rate × stroke volume

Clinical Manifestations of Abnormal Cycle Mechanics

• Dyspnea on exertion: Results from elevated diastolic filling pressures (pulmonary edema) due to diastolic dysfunction or reduced ejection fraction
• Orthopnea and paroxysmal nocturnal dyspnea: Reflect elevated left atrial/pulmonary venous pressures when supine (loss of gravitational advantage), classic in acute decompensated heart failure
• Fatigue and exercise intolerance: Result from reduced cardiac output due to decreased stroke volume (systolic dysfunction) or reduced diastolic filling (atrial fibrillation, mitral stenosis)
• Syncope: May result from arrhythmia-induced loss of atrial contraction or severe aortic stenosis (fixed afterload preventing compensatory increase in contractility)
• Palpitations: Often associated with arrhythmias disrupting normal cycle mechanics; patients may perceive ectopic atrial contraction (S4 gallop) or loss of atrial kick
• Peripheral edema and hepatomegaly: Reflect elevated right-sided filling pressures from right ventricular dysfunction or pulmonary hypertension
• Displaced apical impulse: Indicates ventricular dilatation (increased end-diastolic volume), shifting the point of maximal impulse laterally and inferiorly
• Prominent or palpable S3 or S4: Gallops indicate abnormal ventricular compliance; S3 ("Kentucky" mnemonic for S3-S2-S1 cadence) in systolic dysfunction; S4 in diastolic dysfunction

Electrocardiography: Temporal-Electrical Correlation

• P wave (atrial depolarization, atrial systole initiation): Duration 0.08-0.12 seconds; peaked P waves indicate right atrial enlargement (e.g., pulmonary hypertension), biphasic P waves indicate left atrial enlargement (e.g., mitral stenosis)
• PR interval (AV nodal conduction): 0.12-0.20 seconds; reflects time from atrial depolarization to ventricular depolarization. First-degree AV block (PR >0.20 s) indicates delayed conduction; second-degree or third-degree AV block eliminates or severely delays atrial contribution to ventricular filling, reducing preload
• QRS complex (ventricular depolarization): 0.06-0.10 seconds; widening suggests conduction delay (bundle branch block, ventricular ectopy). QRS voltage reflects left ventricular mass; increased voltage indicates left ventricular hypertrophy
• QT interval (ventricular depolarization and repolarization): Should be <half the preceding RR interval at heart rates >60 bpm. Prolonged QT increases risk of torsades de pointes
• ST segment and T wave (ventricular repolarization): Ischemia/infarction causes ST elevation or depression; T-wave inversion indicates repolarization abnormality (ischemia, hypertrophy, or pulmonary embolism). Peaked T waves indicate hyperkalemia; flattened T waves suggest hypokalemia

Echocardiography: Structural and Functional Assessment

• M-mode echocardiography: Assesses ventricular wall thickness (normal LV wall 8-12 mm), fractional shortening (normal 25-35%, correlates with EF), septal/posterior wall motion
• Two-dimensional (2D) echocardiography: Visualizes all four chambers, valve leaflet motion, regional wall motion abnormalities (segmental hypokinesis/akinesis in ischemia), and pericardial disease
• Doppler echocardiography:
• Pulsed-wave Doppler measures mitral inflow velocities, reflecting diastolic function: Early mitral inflow (E wave, early diastolic filling velocity) and atrial contribution (A wave, late diastolic filling). E/A ratio >1 is normal; E/A <1 (grade I diastolic dysfunction) reflects impaired relaxation
• Tissue Doppler imaging (TDI) measures myocardial wall velocities; E' (early diastolic mitral annular velocity) <8 cm/s indicates impaired relaxation; E/E' >14 predicts elevated filling pressures
• Continuous-wave Doppler quantifies valve regurgitation severity and assesses stenotic valve gradients using modified Bernoulli equation (ΔP = 4v²)
• Ejection fraction calculation: EF = (EDV - ESV)/EDV; normal EF 50-70%; reduced EF <40% defines systolic dysfunction; borderline 40-49% (HFmrEF)

Cardiac Hemodynamics: Pressure and Volume Assessment

• Pulmonary artery catheterization (Swan-Ganz): Directly measures right atrial pressure (CVP, 2-8 mmHg), pulmonary artery pressures (normal 25/10, mean 15 mmHg), pulmonary capillary wedge pressure (PCWP, normal 4-12 mmHg, reflects left atrial pressure), and cardiac output (thermodilution)
• Left heart catheterization: Measures left ventricular pressures and ventriculography visualizes systolic function; normal LVEDP 4-12 mmHg. Elevated LVEDP (>18 mmHg) indicates diastolic dysfunction or systolic dysfunction with elevated filling pressures
• Pressure-volume analysis: End-systolic elastance (slope of ESPVR) and Tau (relaxation time constant) quantify contractility and relaxation independent of loading conditions

Cardiac Biomarkers (Stress/Dysfunction Indicators)

• B-type natriuretic peptide (BNP) and NT-proBNP: Elevated with ventricular stretch from increased diastolic or systolic pressures; BNP >100 pg/mL suggests heart failure (cutoff age-adjusted). Serial measurements assess response to therapy
• Troponin: Elevated with myocardial necrosis (acute MI); ischemia without necrosis produces negative troponin with abnormal ECG or clinical symptoms
• Myoglobin: Non-specific marker of myocardial injury, rises within 2-3 hours of infarction

Exercise Testing and Stress Assessment

• Treadmill ECG stress testing: Reveals ischemia-induced ST depression during exertion (indicates exercise-induced afterload mismatch in systolic dysfunction or reduced coronary reserve). Duke treadmill score predicts prognosis
• Stress echocardiography: Assesses wall motion response to dobutamine or exercise; dyskinesis during stress indicates inducible ischemia
• Cardiac MRI with stress perfusion: Gold standard for viability assessment in post-infarction cardiomyopathy; late gadolinium enhancement indicates scar tissue

Optimizing Preload

• Diuretics (furosemide, torsemide): Reduce intravascular volume, decreasing end-diastolic volume and diastolic pressures; first-line for pulmonary edema. However, excessive diuresis reduces preload below optimal Frank-Starling point, paradoxically reducing stroke volume and cardiac output. Monitor orthostatic vital signs and renal function (creatinine, electrolytes)
• Vasodilators (nitrates, hydralazine): Reduce venous return and preload (nitrates via venous smooth muscle relaxation); particularly useful in acute decompensated heart failure with pulmonary edema
• Fluid administration: Cautious IV fluids or saline bolus in hypovolemic shock or severe sep

Complications of disordered cycle mechanics

• Acute cardiogenic pulmonary edema — emergency: any process that raises left ventricular end-diastolic pressure (impaired relaxation, acute mitral regurgitation, loss of atrial kick) transmits pressure retrograde to the pulmonary capillaries, exceeding the oncotic gradient. Signaled by orthopnea, diffuse rales, and elevated BNP/NT-proBNP; the ACC/AHA/HFSA 2022 Heart Failure Guideline directs IV loop diuretic and, when blood pressure permits, vasodilator therapy.
• Subendocardial ischemia from shortened diastole — emergency when accompanied by ischemic ECG changes: the left ventricle is perfused almost entirely in diastole, so tachycardia disproportionately truncates coronary filling time while raising demand. Signaled by rate-dependent ST depression and angina during any tachyarrhythmia.
• Hemodynamic collapse with loss of AV synchrony — emergency: rapid atrial fibrillation, ventricular tachycardia, or complete heart block abolishes the timed atrial contribution to filling. Signaled by cannon a waves, an irregular pulse with variable S1 intensity, hypotension; per the 2023 ACC/AHA/ACCP/HRS Atrial Fibrillation Guideline, unstable AF warrants urgent cardioversion.
• Ventricular fibrillation / pulseless VT — emergency: electrical chaos abolishes coordinated contraction, so the pressure-volume loop collapses. Immediate defibrillation per AHA ACLS; these are the shockable rhythms.
• Tamponade physiology — emergency: pericardial pressure abolishes the rapid-filling phase, producing an absent y descent, pulsus paradoxus, and equalized diastolic pressures; treatment is pericardiocentesis.
• Tachycardia-mediated cardiomyopathy: sustained loss of filling time and energetic inefficiency dilate the ventricle; signaled by new low EF that improves with rate control.

Complications of therapy

• Over-diuresis: preload falls below the optimal Frank–Starling point, dropping stroke volume; signaled by rising creatinine/BUN:creatinine ratio, orthostatic hypotension, and hypokalemia that can precipitate torsades de pointes.
• Nitrates in preload-dependent states: severe aortic stenosis, hypertrophic obstructive cardiomyopathy, tamponade, and right ventricular infarction depend on filling pressure — nitrate-induced venodilation causes abrupt syncope or shock (emergency). Nitrates with a PDE5 inhibitor produce refractory hypotension.
• Negative inotropes: beta blockers or non-dihydropyridine calcium channel blockers started during acute decompensation further depress dP/dt; signaled by worsening congestion and low output.

• Systole is bracketed by the heart sounds: S1 marks mitral/tricuspid closure at the onset of isovolumetric contraction; S2 marks semilunar closure at the onset of isovolumetric relaxation. During both isovolumetric phases all four valves are closed and volume is constant — the most commonly tested point on the Wiggers diagram.
• Diastole is when the left ventricle is perfused: any stem featuring tachycardia plus angina is testing shortened diastolic coronary filling time. This also explains why rate control, not inotropy, is the therapeutic lever in ischemia and in mitral stenosis.
• Atrial kick and the S4: an S4 requires atrial contraction against a stiff ventricle, so S4 cannot exist in atrial fibrillation. Loss of the atrial kick is most catastrophic where filling is already impaired — mitral stenosis, LVH/HFpEF, restrictive cardiomyopathy.
• Jugular venous waveform: the y descent corresponds to rapid ventricular filling after AV valve opening. Absent y descent suggests tamponade; a steep, deep y descent with a square-root sign suggests constrictive pericarditis — the classic paired distractor.
• Contractility is the ESPVR slope, not the ejection fraction: end-systolic elastance is load-independent, whereas EF falls with increased afterload alone. Do not equate a low EF with intrinsically depressed contractility.
• S2 splitting: physiologic splitting widens on inspiration; fixed wide splitting is the buzzword for atrial septal defect, while paradoxical splitting (narrowing on inspiration) indicates delayed aortic closure — severe aortic stenosis or left bundle branch block.
• Single best next step for exertional dyspnea with a normal EF: transthoracic echocardiography with Doppler (E/A ratio, tissue Doppler E/e′) to demonstrate impaired relaxation, per ACC/AHA/HFSA 2022 Heart Failure Guideline diagnostic framing — not a repeat ECG or empiric bronchodilator.
• Common distractor: an S3 is a normal high-flow finding in children, young adults, and pregnancy, but in an adult over 40 it signals a dilated or volume-overloaded ventricle. Also remember that guideline-directed HFrEF therapy is four classes — ARNI (or ACEI/ARB), beta blocker, MRA, and SGLT2 inhibitor — not three.